JP2020534272A - Transdermal preparation - Google Patents

Abstract

The present disclosure is directed to transdermal compositions comprising isothiocyanates or isocyanates. [Selection diagram] None

Description

[0001] Cross-reference to related applications This application claims the interests of US Provisional Patent Application No. 62 / 559,156 filed on September 15, 2017, which is incorporated herein by reference in its entirety. ..

[0002] Transdermal administration of therapeutic agents has many advantages, including convenience and avoidant gastrointestinal metabolism. However, in the absence of permeation enhancers, many therapeutic agents are unable to penetrate the skin at therapeutically effective concentrations. Therefore, a composition that promotes the permeation of the therapeutic agent into the skin is required.

[0003] Therapeutic agents that are advantageously delivered transdermally include isothiocyanates and isocyanates. Such compounds are therapeutically useful due to their anti-cancer activity. For example, Wattenberg LW, Inhibition of carcinogen-induced neoplasia by sodium cyanate, tert-butyl isocyanate, and benzyl isothiocyanate administered subsequent to carcinogen exposure, Cancer Research, 8 January 1, 1981; 41 (8): 2991-4 page; Hecht SS, Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism, The Journal of cancer, The Journal of cancer, March 1, 1999; 129 (3) Human metabolism and excretion of cancer chemoprotractive group isothiocyanates of isothiocyanates of cancer1 Cancer; Cancer12 Cancer, Cancer12 Cancer, Cancer12 Cancer, Cancer Et al., Phenethyl isothiocyanate: A comprehensive review of anti-cancer mechanisms, Biochim Biophys Acta, December 2014; 1846 (2): 405-424; Et al., "Molecular Targets of Isothiocyanates in Cancer: Recent Advances." Molecule nutrition & food reserve 58.8 (2014): 1685-1707.

[0004] In terms of chemotherapeutic and chemoprotective activity of isothiocyanates and isocyanates, compositions that promote skin permeation of isothiocyanates and isocyanates are needed.

[0005] The present disclosure relates to compositions comprising a first component, a second component, a C _2-10 alkyl alcohol, and an organic acid having 1 to 25 carbon atoms, and a therapeutic agent. And a second component as well as therapeutic agents are further defined herein. Methods for making and using these compositions are also described.

[0006] The present disclosure can be more easily understood by reference to the following detailed description of the desired embodiments and examples contained herein. In the specification below and the claims that follow, some terms with the following meanings are referred to.

[0007] As used herein and in the claims, the term "comprising" is used in embodiments of "consisting of" and "consisting essently of". Can include embodiments of. The terms "comprise", "include", "having", "has", "can", "contin", and variants thereof. As used herein, it is intended to be a non-limiting transitional phrase, term or word that requires the presence of a specified component / step and allows the presence of other components / steps. However, such statements should also be construed as describing compositions or methods such as the listed ingredients / steps "consisting of" and "consisting essentially of", which are specified. Allows the presence of components / steps only, with any impurities that can arise from them, but excludes other components / steps.

[0008] Unless indicated to the contrary, the numbers are the same with the same number of significant figures, and less than the experimental error of the conventional measurement techniques of the form described in this application to determine the values. It should be understood that it contains numbers that differ from the values listed only.

[0009] All ranges disclosed herein include end points described and can be combined independently (eg, the range "2-10" includes end points 2 and 10). , And includes all intermediate values). The end points and arbitrary values of the ranges disclosed herein are not limited to their exact ranges or values, and they are sufficiently ambiguous and include values that approximate these ranges and / or numerical values.

[0010] As used herein, terms indicating approximation can be applied to modify any quantitative description that may change without causing changes to the relevant underlying functionality. Therefore, the values modified by terms such as "about" and "substantially" may not necessarily be limited to the exact values identified. In at least some examples, the word for approximation may correspond to the accuracy of the instrument measuring the value. The modifier "about" should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the phrase "about 2 to about 4" also discloses the range of "2 to 4". The term "about" can refer to plus 10% or minus 10% of the indicated number. For example, "about 10%" can indicate a range of 9% to 11%, and "about 1" can mean 0.9 to 1.1. Other meanings of "about" may be apparent from the context, such as rounding, in which case, for example, "about 1" may mean 0.5 to 1.4.

[0011] As used herein, "alkyl" is the indicated number of carbon atoms, typically 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 or Refers to straight and branched chains with 1 to 7 carbon atoms. For example, C _1-6 alkyls include both straight chain and branched chain alkyls of 1-6 carbon atoms. When an alkyl residue with a particular number of carbons is nominated, it is intended to include all branched and linear types with that number of carbons. Thus, for example, "butyl" means including n-butyl, sec-butyl, isobutyl and t-butyl, and "propyl" includes n-propyl and isopropyl. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl. Including pentyl and so on. The alkyl group may be optionally substituted with one or more halogen atoms (F, Cl, Br or I), a hydroxy group, an alkoxy group or a methylsulfinyl (ie, CH _3- S (O)-) group. ..

[0012] As used herein, "aryl", when used alone or as part of a substituent, is monocyclic or bicyclic with 5 or 10 carbon atoms in the ring. Refers to the aromatic hydrocarbon ring structure of, in which one or more carbon atoms in the ring are optionally substituted. Substituents may contain one or more halogen atoms, -C _1-6 alkyl groups or -C _1-6 alkoxyl groups. Halogen atoms include chlorine, fluorine, bromine and iodine. The C _1-6 alkoxyl groups include, for example, methoxy, ethoxy, propoxy and the like. Examples of aryl groups (substituted and unsubstituted) are phenyl, naphthyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, iodophenyl, chlorofluorophenyl, fluoronaphthyl, difluoronaphthyl, chloronaphthyl, bromonaphthyl, iodine. Includes naphthyl, methylphenyl, ethylphenyl, (trifluoromethyl) phenyl and the like.

[0013] The term _"C 1 -C ₆ alk (alk)" when used alone or as part of a substituent group, aliphatic having 1,2, 3,4, 5 or 6 carbon atoms It refers to a group linker and includes, for example, −CH ₂ −, −CH (CH ₃ ) −, −CH (CH ₃ ) −CH ₂ − and −C (CH ₃ ) ₂ −. In some embodiments, C ₁ -C ₆ alk may be substituted with one or more substituents.

[0014] As used herein, "alkenyl" refers to an unsaturated branched or straight chain alkyl group having at least one carbon-carbon double bond. The alkenyl group can be either a cis or trans configuration for the double bond. The alkenyl group may be an aromatic group, for example a phenyl moiety or a phenylene moiety. Common alkenyl groups are, but are not limited to, ethenyl; propenyls such as propa-1-en-1-yl, propa-1-en-2-yl, propa-2-en-1-yl (allyl). ), Propa-2-en-2-yl; butenyl, eg, porcine-1-en-1-yl, porcine-1-en-2-yl, 2-methyl-propa-1-en-1-yl, Pig-2-en-1-yl, Pig-2-en-1-yl, Pig-2-en-2-yl, Pig-1,3-dien-1-yl, Pig-1,3-diene- 2-Il; Including phenylene and the like. In certain embodiments, the alkenyl group has 2 to 20 carbon atoms.

[0015] As used herein, "alkynyl" is an unsaturated branch with at least one carbon-carbon triple bond derived by removing two hydrogen molecules from adjacent carbon atoms of the parent alkyl. Refers to a chain or straight chain alkyl group. Common alkynyl groups are, but are not limited to, ethynyl; propynyl, eg, propa-1-in-1-yl, propa-2-in-1-yl; butynyl, eg, porcine-1-in-1. -Il, porcine-1-in-3-yl, porcine-3-in-1-yl and the like are included. In certain embodiments, the alkynyl group has 2 to 20 carbon atoms.

[0016] As used herein, the term "treatment" or "treatment" (and various forms thereof) includes prophylactic (eg, prophylactic), curative or palliative treatment. As used herein, the term "treating" includes alleviating or alleviating at least one adverse or negative effect or symptom of a condition, disease or disorder. This condition, disease or disorder can be cancer.

[0017] As used herein and throughout the present disclosure, the term "effective amount" is effective at the dosage and duration required to achieve the desired result for the treatment of the associated disorder, condition or side effect. Refers to a large amount. The effective amount of an ingredient of the present invention is the function of the particular compound, ingredient or composition selected, the route of administration and the ingredient to elicit the desired result of the individual, as well as the severity of the disease stage or condition alleviated. Factors such as degree, individual hormone level, age, gender, weight, current stage of the patient, and severity of pathological condition during treatment, concomitant medications or special diets subsequently performed by a particular patient, and It should be understood that other factors recognized by those skilled in the art will vary from patient to patient with appropriate medication taken at the discretion of the attending physician. Dosage forms may be adjusted to provide improved therapeutic response. Effective amounts also outweigh the therapeutically beneficial effects of any toxic or detrimental effect of the ingredient.

[0018] “Pharmaceutically acceptable” means, within appropriate medical judgment, without excessive toxicity, irritation, allergic response or complications of other problems, and in a reasonable benefit / risk ratio. Refers to their compounds, substances, compositions and / or dosage forms suitable for contact with matching human and animal tissues.

[0019] The present disclosure is directed to compositions that promote and / or enhance percutaneous penetration of therapeutic agents through the skin. As used herein, the term "percutaneous penetration" includes both percutaneous and transmucosal delivery, that is, translocation through the skin or mucosal tissue and into the bloodstream. As used herein with respect to percutaneous permeation, the term "enhancing" refers to an increase in the rate at which a therapeutic agent permeates skin or mucosal tissue and enters the bloodstream. These compositions include a first component, a second component, alcohols, organic acids, therapeutic agents and optionally water.

[0020] According to the present disclosure, the first component is
-Compound of formula (I):
R- (OCH ₂ CH ₂ ) _y- OH (I)
(In the formula, R is C _1-20 alkyl, C _2-20 alkenyl, or C _2-20 alkynyl and y is 1-25),
− Primary hydroxyl group-terminated tetrafunctional block copolymer surfactant,
− Sorbitan derivative,
− C _8-10 alkylammonium salt,
-Compound of formula (II):
HO- (CH ₂ CH ₂ O) _m- C (CH ₃ ) (C ₄ H ₉ ) -C ≡ C-C (CH ₃ ) (C ₄ H ₉ )-(OCH ₂ CH ₂ ) _n- OH (II )
(In the formula, m and n are 1 to 25, respectively),
Or include a combination thereof.

[0021] In a preferred embodiment of the present disclosure, the first component is a compound of formula (I). In some embodiments, R is C _1-20 alkyl and may be either straight chain or branched chain alkyl. Preferred compounds of formula (I) in which R is C _1-20 alkyl are, for example, seto macrogol 1000, octadecane-1-ol ethoxylated, polyoxyethylene (12) tridecyl ether, polyoxyethylene (10) tri. Decyl ether, fatty alcohol polyoxyethylene ether, polyoxyethylene branched nonylcyclohexyl ether (Triton N-101), nonaethylene glycol monododecyl ether, 23-{[4- (2,4,4-trimethyl-2-pentanyl)) Cyclohexyl] oxy} -3,6,9,12,15,18,21-Heptaoxatricosan-1-ol and combinations thereof. Nonaethylene glycol monododecyl ether is particularly preferred.

[0022] In other embodiments, R is C _2-20 alkenyl and may be either straight chain or branched chain alkenyl. Preferred compounds of formula (I) in which R is C _2-20 alkenyl include, for example, polyoxyl (10) oleyl ether, polyethylene glycol tert-octylphenyl ether (Triton X-100) and combinations thereof.

[0023] In yet another embodiment, R is a C _2-20 alkynyl and may be either a straight chain or a branched chain alkynyl.

[0024] In those embodiments where the first component is a compound of formula (I), y is 1-25. In a preferred embodiment, y is 5 to 15, preferably 8 to 10, and particularly preferably 9. In other embodiments, y is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21. , 22, 23, 24 or 25.

[0025] In another aspect of the present disclosure, the first component is a primary hydroxyl group-terminated tetrafunctional block copolymer surfactant. Such compounds are commercially available under the trade name "TETRONIC ™" and include ethylenediamine tetrakis (ethoxylate-block-propoxylate).

[0026] In other embodiments of the present disclosure, the first component is a sorbitan derivative, eg, polyoxyethylene sorbitan tetraoleate, 1,4-anhydro-6-O-palmitoyl-D-glucitol (sorbitol). Monohexadecanoate), polyethylene glycol sorbitan monolaurate (eg, TWEEN® 20, TWEEN® 40, TWEEN® 60, TWEEN® 85) and combinations thereof. ..

[0027] In still another embodiment of the present disclosure, the first component _is a _{C 8 to 10} alkyl ammonium salts, for example, methyl trialkyl _(C 8 _{-C 10)} ammonium chloride (ADOGEN (R) 464) Is.

[0028] In another embodiment, the first component is a compound of formula (II).

[0029] The compositions of the present disclosure may contain from about 0.1% to about 40% by volume of the first component. In a preferred embodiment, the composition comprises from about 1% to about 40% by volume of the first component. In other embodiments, the composition comprises from about 0.1% to about 5% by volume of the first component. For example, the composition is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2 , 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 , 37, 38, 39 or about 40% by volume of the first component.

[0030] According to the present disclosure, the composition also comprises a second component, the second component of which is:
− Compound of formula (III):
^{R 2 -N (R 1) -C} (O) -R 3 (III)
(In the formula, each R ¹ is independently H or C _1-3 alkyl.
R ² and R ³ are independently C _1-7 alkyl, or together with the atoms to which they are attached form a lactam with 3 to 10 carbon atoms),
− Sulfoxide,
− Urea,
− Ethyl acetate,
Or include combinations thereof.

[0031] In a preferred embodiment, the second component is a compound of formula (III). In some embodiments, R ¹ is H. In other embodiments, R ¹ is methyl, ethyl, propyl or isopropyl, with particular preference being methyl.

[0032] In those embodiments where R ² and R ³ are independently C _1-7 alkyl, each of R ² and R ³ is independently methyl, ethyl, propyl, isopropyl, butyl, s-butyl. , T-butyl, pentyl, hexyl or heptyl.

[0033] Preferably, R ² and R ³ form a lactam with 3 to 10 carbon atoms, together with the atoms to which they are attached. For example, the lactam may contain 3, 4, 5, 6, 7, 8, 9 or 10 carbons, which may be part of the lactam ring or form an outer ring branch. Examples of preferred lactams include pyrrolidones, such as 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone and 1-ethyl-2-pyrrolidone. Preferably, the lactam is 1-methyl-2-pyrrolidone or 2-pyrrolidone.

[0034] In some embodiments, the second component is sulfoxide, eg, dimethyl sulfoxide.

[0035] In other embodiments, the second component is urea, eg, imidazolidinone.

[0036] The composition of the present disclosure may contain a second component of about 0.01% by volume to about 10% by volume. In a preferred embodiment, the composition comprises from about 0.01% to about 5% by volume a second component. In other embodiments, the composition comprises from about 0.01% to about 4% by volume a second component. For example, the composition is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4 It may contain a second component of .5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or about 10% by volume.

[0037] In some embodiments of the present disclosure, the volume ratio of the first component to the second component is about 10: 1 to about 4: 1.

[0038] According to the present disclosure, the composition also comprises a C _2-10 alkyl alcohol. Alcohols used in the compositions of the present disclosure include C _2-10 alkyl alcohols having at least one OH moiety or at least two OH moieties. For example, preferred alcohols include glycerol, propylene glycol, ethanol, isopropanol, 1-propanol, butanol, t-butanol, pentanol, 1-octanol and combinations thereof, with ethanol being particularly preferred.

[0039] The compositions of the present disclosure may contain from about 0.1% to about 50% by volume of C _2-10 alkyl alcohols. In a preferred embodiment, the composition comprises from about 1% to about 50% by volume of C _2-10 alkyl alcohol. In other embodiments, the composition comprises from about 0.1% to about 5% by volume of C _2-10 alkyl alcohol. For example, the composition is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2 , 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 , 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or about 50% by volume of C _2-10 alkyl alcohol.

[0040] According to the present disclosure, the composition also comprises an organic acid having 1 to 25 carbon atoms. For example, the organic acids used in the compositions of the present disclosure include acetic acid, ascorbic acid, lactic acid, glycolic acid, propionic acid and combinations thereof.

[0041] Other organic acids used in the present disclosure include fatty acids. As used herein, the term "fatty acid" has the usual meaning as understood by those skilled in the art and includes molecules having carboxylic acid groups and hydrocarbon chains. The description of the number of carbon atoms in a fatty acid described herein refers to the number of carbon atoms in a fatty acid's hydrocarbon chain, regardless of whether the hydrocarbon chain is straight or branched.

[0042] As used herein, the term "fatty acid" includes saturated fatty acids that do not contain double or triple bonds in the hydrocarbon chain. Saturated fatty acids are not limited to these, but propionic acid (C3) (eg, C3 indicates that propionic acid has three carbon atoms in its hydrocarbon chain. Hydrocarbons of other examples of fatty acids. The number of carbon atoms in the chain is expressed in the same manner herein), butyric acid (C4), valerate (C5), caproic acid (C6), enanthic acid (C7), capric acid (C8), Pelargonic acid (C9), Capric acid (C10), Undecic acid (C11), Lauric acid (C12), Tridecic acid (C13), Myristic acid (C14), Pentadecic acid (C15), Palmitic acid (C16), Margaric acid (C17), stearic acid (C18), isostearic acid (C18), nonadesyl acid (C19), arachidic acid (C20), henicosyl acid (C21), behenic acid (C22), tricosyl acid (C23), lignoseric acid (C24) ), Pentacosylic acid (C25), cellotic acid (C26), heptacosylic acid (C27), montanic acid (C28), nonacosylic acid (C29), melisic acid (C30), henatriacontylic acid (C31), laxeronic acid ( Examples include C32), psylic acid (C33), gedic acid (C34), celloplastinic acid (C35) and hexatriacontylic acid (C36).

[0043] As used herein, the term "fatty acid" is a monounsaturated fatty acid containing one double or triple bond in a hydrocarbon chain as well as multiple double bonds in a hydrocarbon chain. Also includes polyunsaturated fatty acids containing and / or triple bonds. Such acids include, but are not limited to, omega-3 fatty acids, omega-6 fatty acids, omega-9 fatty acids, as well as fatty acids such as myristoleic acid and palmitoleic acid, and conjugated fatty acids. Examples of monounsaturated fatty acids and polyunsaturated fatty acids are, but are not limited to, (a) omega-3 fatty acids, such as hexadecatrine acid (C16: 3) (eg, C16: 3 is hexa). It is shown that decatorionic acid has 16 carbon atoms and 3 double bonds in its hydrocarbon chain. The number of carbon atoms and double bonds in the hydrocarbon chain of unsaturated fatty acids in other examples is (Displayed in the same fashion herein), alpha linolenic acid (C18: 3) and eicosapentanoic acid (20: 5), etc. (b) Omega 6 fatty acids, such as linoleic acid (18: 2). ), Docosazienoic acid (C22: 2), arachidonic acid (C20: 4) and tetracosatetraenoic acid (C24: 5), (c) omega-9 fatty acids such as oleic acid (C18: 1), eicosenoic acid (C20). 1) and nevronic acid (C24: 1), and (d) conjugated fatty acids such as rumenic acid (C18: 2), eleostatic acid (C18: 3) and lumerenoic acid (C18: 3). C18: 3) can be mentioned.

[0044] As used herein, the term "fatty acid" also includes branched fatty acids. Examples of branched fatty acids include, but are not limited to, monomethyl branched fatty acids such as 14-methylpentadecanoic acid, 6-methylcapric acid, 4-methyl-3-pentenoic acid (pyroterebic acid), 2-methyl-2E-. Butenoic acid (tigric acid), 2-methyl-2Z-butenoic acid (angelic acid), multimethyl branched fatty acid, isoprenoid fatty acid (vitatalactone, all-trans retinoic acid), branched methoxy fatty acid, and hydroxy fatty acid and Other fatty acids include, for example, 2-hydroxyoctanoic acid and 4-oxopentanoic acid.

[0045] The compositions of the present disclosure may contain from about 0.01% to about 15% by volume of organic acids. In some embodiments, the composition comprises from about 1% to about 15% by volume of organic acid. In a preferred embodiment, the composition comprises from about 0.01% to about 5% by volume of organic acid. In other embodiments, the composition comprises from about 0.01% to about 3% by volume of organic acid. For example, the composition is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4 .5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5 , 13, 13.5, 14, 14.5 or about 15% by volume of organic acid.

[0046] According to the present disclosure, the composition is a therapeutic agent of formula (IV):
R ^4- N = C = Z (IV)
(In the formula, Z is S or O and R ⁴ is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 arc-aryl or aryl).
Also includes.

[0047] In some embodiments, R ⁴ of the compound of formula (IV) will be replaced with one or more substituents. In some embodiments, the substituents on ^{R 4} is a halogen atom (F, Cl, Br or _{I), C 1 to 6} alkoxy _group, a _{C 1 to 6} alkyl group or a methylsulfinyl group.

[0048] In some embodiments, Z of the compound of formula (IV) is S (i.e. sulfur), a compound of formula (IV) is an isothiocyanate of the formula R ⁴ -N = C = S , In the formula, R ⁴ is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 arc-aryl or aryl.

[0049] In embodiments where Z is S and R ⁴ is C _1-6 alkyl, the compound of formula (IV) is an isothiocyanate of formula C _1-6 alkyl-N = C = S. For example, C ₁ alkyl-N = C = S, C ₂ alkyl-N = C = S, C ₃ alkyl-N = C = S, C ₄ alkyl-N = C = S, C ₅ alkyl-N = C = S, C ₆ alkyl-N = C = S, methyl isothiocyanate, substituted methyl isothiocyanate, ethyl isothiocyanate, substituted ethyl isothiocyanate, propyl isothiocyanate, substituted propyl isothiocyanate, butyl isothiocyanate, t-butyl isothiocyanate, substituted Examples thereof include butyl isothiocyanate, pentyl isothiocyanate, substituted pentyl isothiocyanate, hexyl isothiocyanate, and substituted hexyl isothiocyanate. In some embodiments, the C _1-6 alkyl is substituted with one or more methylsulfinyl groups. Therefore, in some embodiments, the compound of formula (IV) is a methylsulfinyl-substituted butyl isothiocyanate. In some embodiments, the compound of formula (IV) is sulforaphane (ie, 1-isothiocianato-4-methylsulfinylbutane).

[0050] Z is S, and in the embodiment ^{wherein R 4} is _{C 2 to 6} alkenyl, a compound of formula (IV) is an isothiocyanate of the formula _{C 2 to 6} alkenyl -N = C = S, For example, C ₂ alkenyl-N = C = S, C ₃ alkenyl-N = C = S, C ₄ alkenyl-N = C = S, C ₅ alkenyl-N = C = S, C ₆ alkenyl-N = C = S, ethenyl isothiocyanate, substituted ethenyl isothiocyanate, propenyl isothiocyanate, substituted propenyl isothiocyanate, butenyl isothiocyanate, substituted butenyl isothiocyanate, pentenyl isothiocyanate, substituted pentenyl isothiocyanate, hexenyl isothiocyanate, substituted hexenyl isothiocyanate And so on. In some embodiments, the C _2-6 alkenyl group is an allyl group. Thus, in some embodiments, the compound of formula (IV) is allyl isothiocyanate (ie, CH ₂ = CH-CH _2- N = C = S).

[0051] In an embodiment where Z is S and R ⁴ is C _1-6 arc-aryl, the compound of formula (IV) is an iso of formula aryl-C _1-6 arc-N = C = S. It is an isothiocyanate, for example, aryl-C ₁ arc-N = C = S, aryl-C ₂ arc-N = C = S, aryl-C ₃ arc-N = C = S, aryl-C ₄ arc-N =. C = S, aryl-C ₅ arc-N = C = S, aryl-C ₆ arc-N = C = S, benzyl isothiocyanate (ie, phenyl-CH _2- N = C = S), substituted benzyl isothiocyanate , Phenethyl isothiocyanate (ie, phenyl-CH ₂ CH _2- N = C = S, "PEITC"), substituted phenethyl isothiocyanate, 3-phenylpropyl isothiocyanate, substituted 3-phenylpropyl isothiocyanate and the like.

[0052] In some embodiments, the compound of formula (IV) is phenethyl isothiocyanate. In another embodiment, the compound of formula (IV) is a substituted phenethyl isothiocyanate in which the phenethyl group is substituted with a halogen, C _1-6 alkoxy or C _1-6 alkyl.

[0053] In some embodiments, the compound of formula (IV) is a benzyl isothiocyanate. In another embodiment, the compound of formula (IV) is a substituted benzyl isothiocyanate in which the benzyl group is substituted with a halogen, C _1-6 alkoxy or C _1-6 alkyl.

[0054] Z is S, and in the embodiment wherein R ⁴ is aryl, the compounds of formula (IV) is an isothiocyanate of the formula aryl -N = C = S, for example, phenyl isothiocyanate (i.e., Phenyl-N = C = S), substituted phenyl isothiocyanate (ie, substituted phenyl-N = C = S) and the like. In some embodiments, the substituted phenyl-N = C = S phenyl group is substituted with halogen, C _1-6 alkoxy or C _1-6 alkyl.

[0055] In some embodiments, Z of the compound of formula (IV) is O (i.e., oxygen), compounds of formula (IV) is an expression ^R 4 -N = C = O isocyanates, In the formula, R ⁴ is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 arc-aryl or aryl.

[0056] Z is O, and in the embodiment ^{wherein R 4} is _{C 1 to 6} alkyl, a compound of formula (IV) is an expression _{C 1 to 6} alkyl -N = C = O of isocyanates, for example, , C ₁ alkyl-N = C = O, C ₂ alkyl-N = C = O, C ₃ alkyl-N = C = O, C ₄ alkyl-N = C = O, C ₅ alkyl-N = C = O , C ₆ alkyl-N = C = O, methyl isocyanate, substituted methyl isocyanate, ethyl isocyanate, substituted ethyl isocyanate, propyl isocyanate, substituted propyl isocyanate, butyl isocyanate, substituted butyl isocyanate, pentyl isocyanate, substituted pentyl isocyanate, hexyl isocyanate, substituted Hexyl isocyanate and the like can be mentioned. In some embodiments, the compound of formula (IV) is t-butyl isocyanate.

[0057] In embodiments where Z is O and R ⁴ is C _2-6 alkenyl, the compound of formula (IV) is an isocyanate of formula C _2-6 alkenyl-N = C = O, eg , C ₂ alkenyl-N = C = O, C ₃ alkenyl-N = C = O, C ₄ alkenyl-N = C = O, C ₅ alkenyl-N = C = O, C ₆ alkenyl-N = C = O , Ethenyl isocyanate, substituted ethenyl isocyanate, propenyl isocyanate, substituted propenyl isocyanate, butenyl isocyanate, substituted butenyl isocyanate, pentenyl isocyanate, substituted pentenyl isocyanate, hexenyl isocyanate, substituted hexenyl isocyanate and the like. In some embodiments, the C _2-6 alkenyl group is an allyl group. Thus, in some embodiments, the compound of formula (IV) is allyl isocyanate (ie, CH ₂ = CH-CH _2- N = C = O).

[0058] Z is O, and ^{R 4} is _{C 1 to 6} alk - In embodiment is aryl, the compounds of formula (IV) aryl _{-C 1 to 6} alk -N = C = O isocyanate For example, aryl-C ₁ arc-N = C = O, aryl-C ₂ arc-N = C = O, aryl-C ₃ arc-N = C = O, aryl-C ₄ arc-N = C. = O, aryl-C ₅ arc-N = C = O, aryl-C ₆ arc-N = C = O, benzyl isocyanate (ie, phenyl-CH _2- N = C = O), substituted benzyl isocyanate, phenethyl isocyanate (That is, phenyl-CH ₂ CH _2- N = C = O), substituted phenethyl isocyanate, 3-phenylpropyl isocyanate, substituted 3-phenylpropyl isocyanate and the like can be mentioned.

[0059] In some embodiments, the compound of formula (IV) is phenethyl isocyanate. In another embodiment, the compound of formula (IV) is a substituted phenethyl isocyanate in which the phenethyl group is substituted with a halogen, C _1-6 alkoxy or C _1-6 alkyl.

[0060] In another embodiment, the compound of formula (IV) is benzyl isocyanate. In another embodiment, the compound of formula (IV) is a substituted benzyl isocyanate in which the benzyl group is substituted with a halogen, C _1-6 alkoxy or C _1-6 alkyl.

[0061] Z is O, and in the embodiment wherein R ⁴ is aryl, the compounds of formula (IV) is an expression aryl -N = C = O of isocyanates, for example, phenyl isocyanate (i.e., phenyl - N = C = O), substituted phenyl isocyanate (that is, substituted phenyl-N = C = O) and the like. In some embodiments, the substituted phenyl-N = C = O phenyl group is substituted with halogen, C _1-6 alkoxy or C _1-6 alkyl.

[0062] When the therapeutic agent of formula (IV) is liquid at standard temperature and standard pressure (0 ° C., absolute pressure 1 bar), the compositions of the present disclosure are from about 0.01% to about 15 volumes. Percentage of therapeutic agents of formula (IV) may be included. In some embodiments, the composition comprises from about 1% to about 15% by volume the therapeutic agent of formula (IV). In a preferred embodiment, the composition comprises from about 0.01% to about 5% by volume the therapeutic agent of formula (IV). In other embodiments, the composition comprises from about 0.01% to about 3% by volume the therapeutic agent of formula (IV). For example, the composition is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4 .5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5 , 13, 13.5, 14, 14.5 or about 15% by volume of the therapeutic agent of formula (IV).

[0063] When the therapeutic agent of formula (IV) is solid at standard temperature and pressure (0 ° C., absolute pressure 1 bar), the compositions of the present disclosure are from about 0.01% to about 15% by weight. % May contain a therapeutic agent of formula (IV). In some embodiments, the composition comprises from about 1% to about 15% by weight of the therapeutic agent of formula (IV). In a preferred embodiment, the composition comprises from about 0.01% to about 5% by weight of the therapeutic agent of formula (IV). In other embodiments, the composition comprises from about 0.01% to about 3% by weight of the therapeutic agent of formula (IV). For example, the composition is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4 .5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5 , 13, 13.5, 14, 14.5 or about 15% by weight of the therapeutic agent of formula (IV).

[0064] In some embodiments, the compositions of the present disclosure also include a second therapeutic agent, which is an anticancer agent. Illustrative anticancer agents that may be present in the compositions of the present disclosure as a second therapeutic agent include 5-fluorouracil, avilateron acetate, acetylcholine, ado-trastuzumab emtancin, afatinib, aldesroykin, exetinib, alemtuzumab, Aritretinoin, aminolevulinic acid, anastrozole, anastrozole, aprepitant, arsenic trioxide, asparaginase erwinia chrysantemi, atezolizumab, axitinib, azacitidine, verinostat, bendamstin, bebashizumab, bexaloten, bikartamide, bleomimycin Brentuximab vedotin, busulfan, cabazitaxel, cabozanthinib, capecitabin, carboplatin, carfilzomib, carmustin, seritinib, setuximab, chlorambusyl, cisplatin, clofarabin, cobimetinib, crizotinib, cyclophosfamid, citalabazine , Daratumumab, dasatinib, daunorubicin, decitabine, defibrotide sodium, degarelix, deniroykin difchitox, denosmab, dexamethasone, dexrazoxane, dihydrotestosterone (DHT), dihydrotestosterone (DHT), dinutuximab, docetaxyl, docetaxyl, doxomab Elibrin mesylate, errotinib, etopocid, everolimus, exemestane, exemestane, filgrastim, fuldarabin phosphate, flutamide, fulvestrant, fulvestrant, gefitinib, gemcitabine, gemtuzumab, gemtuzumab ozogamicin Gosereline, hydroxyurea, ibritsumomabuchiuxetane, ibrutinib, idarubicin, ideraricib, ipofamide, imatinib, imikimod, interferon alpha-2b, ipilimumab, irinotecan, ixavepyrone, ixazomib, lanleotide, lapatizole, lapatinib , Romustin, mechloretamine, megestrol acetate, melfaran, mercaptopurine, mesna, methotrexate, mitomycin C, mitoxanthrone, necitumumab, nerarabin, netupitant, nirotinib, niltamide, Nivolumab, Obinutsumab, Ofatumumab, Olaparib, Omasetaxin mepescusinate, Osimertinib, Oxaliplatin, Ozogamycin, Paclitaxel, Parvocyclib, Parifermin, Pamidronate, Panitumumab, Panovinostat, Pazopanib, Pazopanib, Pazopanib, Panitumumab, Panitumumab, Panitumumab , Pertuzumab, prelyxaform, pomalidomid, ponatinib, pralatrexate, prednison, procarbazine, propranolol, radium dichloride 223, laroxifene, ramsylmab, lasbricase, legorafenib, rituximab, lorapitant, lomidepsine, lomisylutism Sorafenib, snitinib, tarimogen rahelparepbek, tamoxifen, temozolomide, temsirolimus, salidamide, thioguanine, thiotepa, tipiracil, topotecan, tremiphen, tremiphen, tositumomab, trabectedin, tramethinibacetate, trastuzumab, trastuzumab, trastuzumab Included are cracks, vinblastine, vincristine, vinorelbine, bismodegib, bolinostat, ziv-affribercept, zoledronic acid, and pharmaceutically acceptable salts thereof.

[0065] Another anti-cancer agent that may be included in the compositions of the present disclosure is the five components of SM88 (sirolimus, melanin, melanotan, phenytoin and tyrosine isomers) in a preliminary study of 30 patients. [J ClinOncol 31, 2013 (suppl; abstr e22095) and Hoffman et al., GynOncol, 130 (1), showed anti-cancer activity with little or no toxicity when administered together. , 2013, e43]. Thus, in some embodiments, the compositions of the present disclosure contain both a compound of formula (IV) and one or more components of SM88 as a second therapeutic agent.

[0066] In some embodiments, the compositions of the present disclosure include benzyl isothiocyanate or phenethyl isothiocyanate as a compound of formula (IV) and one or more components of SM88 as a second therapeutic agent.

[0067] When the second therapeutic agent is liquid at standard temperature and pressure (0 ° C., absolute pressure 1 bar), the compositions of the present disclosure are from about 0.01% to about 15% by volume. A second therapeutic agent may be included. In some embodiments, the composition comprises from about 1% to about 15% by volume of a second therapeutic agent. In a preferred embodiment, the composition comprises from about 0.01% to about 5% by volume of a second therapeutic agent. In other embodiments, the composition comprises from about 0.01% to about 3% by volume of a second therapeutic agent. For example, the composition is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4 .5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5 , 13, 13.5, 14, 14.5 or about 15% by volume of the second therapeutic agent.

[0068] When the second therapeutic agent is solid at standard temperature and pressure (0 ° C., absolute pressure 1 bar), the compositions of the present disclosure are from about 0.01% to about 15% by weight. A second therapeutic agent may be included. In some embodiments, the composition comprises from about 1% to about 15% by weight of a second therapeutic agent. In a preferred embodiment, the composition comprises from about 0.01% to about 5% by weight of the second therapeutic agent. In other embodiments, the composition comprises from about 0.01% to about 3% by weight of a second therapeutic agent. For example, the composition is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4 .5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5 , 13, 13.5, 14, 14.5 or about 15% by weight of the second therapeutic agent.

[0069] The compositions of the present disclosure may be anhydrous. As used herein, "anhydrous" refers to a composition comprising less than 1% by volume water, preferably less than 0.05% by volume or less than 0.025% by volume. Methods of determining the water content are known in the art.

[0070] The compositions of the present disclosure may include water. In some embodiments, the composition may contain up to 99% by volume of water. In still other embodiments, the composition may comprise 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99% by volume of water. In other embodiments, the composition may comprise 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% by volume water.

[0071] The compositions of the present disclosure comprising water can optionally contain one or more physiologically acceptable salts. Without being bound by any particular theory, the composition can be used to control the amount of salt present by using the concentration of salt that is usually inversely correlated with the depth of permeation. It is considered that the depth of transmission can be controlled. The salts used in the composition include, but are not limited to, sodium chloride, potassium chloride and mixtures thereof. A preferred form of sodium chloride is a bacteriostatic sodium chloride solution.

[0072] The compositions of the present invention may be designed for administration to the skin or mucosal tissue of a patient in need of treatment. The compositions of the invention can be formulated as gels, transdermal patches, lotions, creams, sprays, mists, emulsions or dispersants. Suitable additives for formulating gels, transdermal patches, lotions, creams, sprays or mists are readily apparent to those skilled in the art and are not limited to stabilizers, emulsifiers, thickeners. Includes adhesives such as antibacterial agents, moisturizers, propellants, spreading agents, polymers and pressure sensitive adhesives. In particular, the additives that can be used to form transdermal gels include, but are not limited to, alcohols, glycols, glycerin, butylated hydroxytoluene (BHT) and water.

[0073] Also a method comprising administering to the skin of a mammal any of the described compositions under effective time and conditions to achieve at least a portion of the composition through the skin. It is within the scope of disclosure. Skin penetration can be measured using techniques known in the art.

[0074] The compositions of the present disclosure can be used to administer a therapeutic agent (eg, a compound of formula (IV)) to a mammal. For example, in a preferred embodiment, these methods apply any of the compositions to mammalian skin for a time sufficient to achieve penetration of the therapeutic agent through at least a portion of the skin. including. Skin penetration of therapeutic agents can be measured using techniques known in the art.

[0075] The present disclosure further includes a method of treating a mammalian cancer in need of treatment of the cancer, wherein the method penetrates through the skin or mucous membrane of an effective amount of a therapeutic agent of formula (IV). Includes applying the compositions of the present disclosure to the skin or mucous membranes of said mammal for a time sufficient to achieve. In some embodiments, the mammal is a human. In some embodiments, the cancer is a non-small cell lung cancer, ovarian cancer, breast cancer, cervical cancer, pancreatic cancer, gastric cancer, brain cancer, liver cancer, testicular cancer, leukemia, lymphoma, worm drop. Cancer, biliary tract cancer, bile duct cancer, colon cancer, colorectal cancer, germ cell tumor, glioma, hodgkin lymphoma, lung cancer, neuroblastoma, prostate cancer, renal cancer, sarcoma, thyroid cancer , Tongue cancer, tongue squamous cell carcinoma or urinary tract cancer. In some embodiments, the cancer is leukemia. In other embodiments, the cancer is lung cancer.

[0076] In some embodiments, the composition of the present disclosure is administered as a component of combination chemotherapy, whereby the composition of the present disclosure is administered in combination with another chemotherapy regimen. Other chemotherapeutic regimens may include administering conventional anti-cancer agents to mammals by any suitable route of administration. As used herein, the term "combination" means that the compositions of the present disclosure and other chemotherapeutic regimens, at some point, both compounds of formula (IV) and conventional anti-cancer agents. It means that it is administered so that it is present in the bloodstream of a mammal. In some embodiments, other chemotherapy regimens give effective amounts of 5-fluorouracil, avilateron acetate, acetylcholine, ado-trastuzumab methanecin, afatinib, aldesroykin, rectinib, alemtuzumab to mammals in need of chemotherapy. , Aritretinoin, aminolevulinic acid, anastrozole, anastrozole, aprepitant, arsenic trioxide, asparaginase erwinia chrysantemi, atezolizumab, axitinib, azacitidine, verinostat, bendamstin, bebashizumab, bexaloten, bicartamide, bleomomyb , Brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, capesitabin, carboplatin, carfilzomib, carmustin, seritinib, setuximab, chlorambusyl, cisplatin, clofarabin, cobimetinib, crizotinib, cyclophosphamide, cryzotinib, cyclophosphamide Mycin, daratumumab, dasatinib, daunorubicin, decitabine, defibrotide sodium, degarelix, deniroykin difchitox, denosmab, dexamethasone, dexrazoxane, dihydrotestosterone (DHT), dinutuximab, docetaxyl, docetaxyl, docetaxyl, docetaxyl , Elibrin mesylate, errotinib, etopocid, everolimus, exemestane, exemestane, filgrastim, fulvestrant, fulvestrant, gefitinib, gemcitabine, gemtuzumab, gemtuzumab ozogamycin, gemtuzumab ozogamycin Gosereline acetate, hydroxyurea, ibritsumomabuchiuxetane, ibrutinib, idarubicin, ideralisib, ifosphamide, imatinib, imikimodo, interferon alpha-2b, ipilimumab, irinotecan, ixavepyrone, ixazomib, lanleotide, lapatizole, lapatinib Leuprolide, romustine, mechloretamine, megestrol acetate, melfaran, mercaptopurine, mesna, methotrexate, mitomycin C, mitoxanthrone, necitumumab, nerarabin, netupitant, nirotini Bu, niltamide, niborumab, obinutuzumab, ofatumumab, olaparib, omacetaxin mepescusinate, osimertinib, oxaliplatin, ozogamycin, paclitaxel, parvocyclib, parifermin, paclitaxel, parvocyclib, parifermin, paclitaxel, panitumumab, panobinostat, panitumumab, panitumumab, panitumumab , Pembrolizumab, pemetrexed, pertuzumab, prelyxaform, pomalidemid, ponatinib, pralatrexate, predonison, procarbazine, propranolol, radium dichloride 223, laroxyphene, lambsilumab, lasbricase, legorafenib, rituximab, lyximab, lyximab, lyximab t, SM88, sonidegib, sorafenib, snitinib, tarimogen rahelparepbek, tamoxyphene, temozolomide, temsirolimus, salidamide, thioguanine, thiotepa, tipiracil, topotecan, tremiphen, tremiphen, tositumumab, trastuzumab, trastuzumab, trastuzumab , Bandetanib, Bemurafenib, Venetocrax, Vincristine, Vincristine, Vinorelbine, Bismodegib, Borinostat, ziv-Afribercept, Zoledronic acid, or pharmaceutically acceptable salts thereof.

[0077] In some embodiments, other chemotherapy regimens administer effective amounts of SM88, cisplatin, adriamycin, etoposide, paclitaxel, metformin, vorinostat or docetaxel to mammals in need of chemotherapy. Including.

[0078] The present disclosure further includes methods for preventing mammalian cancer in need of cancer prevention, wherein the method is at least some of the therapeutic agents of formula (IV) via the skin or mucosa. Includes applying the compositions of the present disclosure to mammalian skin or mucous membranes for a time sufficient to achieve penetration. In some embodiments, the mammal is a human.

[0079] The compositions described herein can be applied to any manageable skin surface. The skin surface of interest includes, but is not limited to, arms, legs, torso, head, neck and the like. The surface area covered with the transdermal formulation according to application is usually sufficient to provide the desired amount of drug administration, and in certain embodiments ranges from about 1 cm ² to about 200 cm ^2. ..

[0080] The compositions described herein can be applied single or multiple times over a given period of time, eg, the course of the disease state being treated, and multiple patches are administered over a given period of time. The dosing schedule can be daily, weekly, biweekly, monthly, etc.

[0081] In some embodiments, the compositions of the present disclosure include one or more additional ingredients in addition to the above ingredients. Additional ingredients include, but are not limited to, transdermal absorption enhancers, preservatives (eg, parabens), antioxidants, stabilizers, fillers containing hydrophilic polymers, crosslinkers and plasticizers.

[0082] The following examples are provided to illustrate the compositions, processes and properties of the present disclosure. The examples are merely exemplary and are not intended to limit this disclosure to the material, condition or process parameters described herein.

Example 1
[0083] Aqueous composition for transdermal administration of the therapeutic agent of formula (IV) Nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone (0.3 mL), ethanol (4 mL), oleic acid (1 mL) ) And water (50 mL) are combined to form a mixture. An effective amount of the therapeutic agent of formula (IV) is combined with the mixture to form a transdermal composition. The transdermal composition is applied to the patient's skin in an amount and time sufficient for the therapeutic agent to penetrate the skin and into the patient's bloodstream to achieve a therapeutic effect.

Example 2
Anhydrous composition for transdermal administration of the therapeutic agent of formula (IV) Nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone (0.3 mL), ethanol (4 mL) and linoleic acid (1 mL) ) Are combined to form a mixture. An effective amount of the therapeutic agent of formula (IV) is combined with the mixture to form a transdermal composition.

Example 3
[0085] Transdermal administration of the therapeutic agent of formula (IV) using an anhydrous composition The therapeutic agent of formula (IV) is sufficient to penetrate the skin and into the patient's bloodstream to achieve a therapeutic effect. The transdermal composition of Example 2 is applied to the patient's skin in an appropriate amount and time.

Example 4
[0086] Aqueous transdermal composition for sensitive tissues The composition of Example 2 (1 mL) is mixed with 99 mL of water. The resulting aqueous composition can be applied to the sensitive tissue, eg, the mucosa, for a time sufficient to allow the therapeutic agent to penetrate into the patient's bloodstream through the sensitive tissue and achieve a therapeutic effect. ..

Example 5
[0087] Aqueous transdermal composition for normal skin The composition of Example 2 (1 mL) is mixed with 49 mL of water. The resulting aqueous composition can be applied to normal skin for a time sufficient to allow the therapeutic agent to penetrate into the patient's bloodstream through normal skin and achieve a therapeutic effect.

Example 6
[0088] Aqueous phenethyl isothiocyanate transdermal composition Nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone (0.3 mL), ethanol (4 mL) and linoleic acid (1 mL) are combined. Phenethyl isothiocyanate (1 mL) (eg, Sigma Aldrich Catalog No. 253731) is then added to form a mixture. The mixture (1 mL) is then combined with 24 mL of water. The resulting aqueous composition can be applied to the skin or tissue for a time sufficient for the phenethyl isothiocyanate to penetrate the skin or tissue and into the patient's bloodstream to achieve a therapeutic effect.

Example 7
[0089] Aqueous benzyl isothiocyanate transdermal composition Combine nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone (0.3 mL), ethanol (4 mL) and linoleic acid (1 mL). Benzyl isothiocyanate (1 mL) (eg, Sigma Aldrich Catalog No. 252492) is added to form a mixture. The mixture (1 mL) is then combined with 24 mL of water. The resulting aqueous composition can be applied to the skin or tissue for a time sufficient for the benzyl isothiocyanate to penetrate the skin or tissue and into the patient's bloodstream to achieve a therapeutic effect.

Example 8
[0090] Aqueous phenethyl isothiocyanate transdermal composition Combine nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone (0.3 mL), ethanol (4 mL) and linoleic acid (1 mL). Phenethyl isothiocyanate (1 mL) (eg, Sigma Aldrich Catalog No. 253731) is then added to form a mixture. The mixture (1 mL) is then combined with 32.3 mL of water. The resulting aqueous composition can be applied to the skin or tissue for a time sufficient for the phenethyl isothiocyanate to penetrate the skin or tissue and into the patient's bloodstream to achieve a therapeutic effect.

Example 9
[0091] Aqueous benzyl isothiocyanate transdermal composition Combine nonaethylene glycol monododecyl ether (3 mL), 1-methyl-2-pyrrolidinone (0.3 mL), ethanol (4 mL) and linoleic acid (1 mL). Benzyl isothiocyanate (1 mL) (eg, Sigma Aldrich Catalog No. 252492) is added to form a mixture. The mixture (1 mL) is then combined with 32.3 mL of water. The resulting aqueous composition can be applied to the skin or tissue for a time sufficient for the benzyl isothiocyanate to penetrate the skin or tissue and into the patient's bloodstream to achieve a therapeutic effect.

Claims (63)

-Therapeutic agent of formula (IV) R ^4- N = C = Z (IV)
(In the formula, Z is S or O and R ⁴ is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 arc-aryl or aryl),
-Compound of formula (I) R- (OCH ₂ CH ₂ ) _y- OH (I)
(In the formula, R is C _1-20 alkyl or C _2-20 alkenyl and y is 1-25),
-Amide of formula (III) R ^2- N (R ¹ ) -C (O) -R ³ (III)
(In the formula, each R ¹ is independently H or C _1-3 alkyl, and R ² and R ³ are lactams having 3 to 10 carbon atoms, along with the atoms to which they are attached. To form),
− C _2-10 alkyl alcohols, as well as
-Organic acid, which is a fatty acid with 1 to 25 carbon atoms,
A composition comprising. The composition according to claim ₁ , wherein R is C _{1 to 20} alkyl. The compounds of formula (I) are seto macrogol 1000, octadecane-1-ol ethoxylated, polyoxyethylene (12) tridecyl ether, polyoxyethylene (10) tridecyl ether, fatty alcohol polyoxyethylene ether, polyoxy. Ethylene-branched nonylcyclohexyl ether, nonaethylene glycol monododecyl ether, 23-{[4- (2,4,4-trimethyl-2-pentanyl) cyclohexyl] oxy} -3,6,9,12,15,18,21 The composition according to claim 2, which is heptaoxatricosan-1-ol or a combination thereof. The composition according to claim 1, wherein the compound of the formula (I) is a nonaethylene glycol monododecyl ether. The composition according to claim 1, wherein R is C _{2 to 20} alkenyl. The composition according to claim 5, wherein the compound of formula (I) is polyoxyl (10) oleyl ether, polyethylene glycol tert-octylphenyl ether, or a combination thereof. The composition according to claim 1, wherein y is 5 to 15. The composition according to claim 1, wherein y is 8 to 10. The composition according to claim 1, wherein y is 9. The composition according to claim 1, wherein R ¹ is methyl, ethyl or propyl. The composition according to claim 1, wherein the lactam is pyrrolidone. The composition according to claim 11, wherein the pyrrolidone is 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone or 1-ethyl-2-pyrrolidone. The composition according to claim 11, wherein the pyrrolidone is 1-methyl-2-pyrrolidone. The composition according to claim 1, wherein the C _2-10 alkyl alcohol is glycerol, propylene glycol, ethanol, isopropanol, 1-propanol, butanol, t-butanol, pentanol, 1-octanol or a combination thereof. The composition according to claim 1, wherein the C _{2 to 10} alkyl alcohol is ethanol. The composition according to claim 1, wherein the fatty acid is a saturated fatty acid, an unsaturated fatty acid or a polyunsaturated fatty acid. Fatty acids are butyric acid, valeric acid, caproic acid, enanthic acid, capric acid, pelargonic acid, capric acid, undecic acid, lauric acid, tridecic acid, myristic acid, pentadecic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, Nonadesyl acid, arachidic acid, henicosyl acid, bechenic acid, tricosyl acid, lignoseric acid, pentacosyl acid, serotic acid, heptacosyl acid, montanic acid, nonacosyl acid, melisic acid, henatriacontyl acid, laxeronic acid, psylic acid, geda The composition according to claim 1, which is an acid, celloplastinic acid or hexatriacontylic acid. Fatty acids are hexadecatrienoic acid, alpha-linolenic acid, eicosapentaenoic acid, linoleic acid, docosadienoic acid, arachidonic acid, tetracosatetraenoic acid, oleic acid, eicosenoic acid, nervonic acid, rumenic acid, eleostearic acid or lumerene acid. The composition according to claim 1. The fatty acids are 14-methylpentadecylic acid, 6-methylcaprylic acid, 4-methyl-3-pentenoic acid (pyroterebic acid), 2-methyl-2E-butenoic acid (tigric acid), 2-methyl-2Z-butenoic acid ( The composition according to claim 1, wherein the composition is angelic acid), bitatalactone (all-trans retinoic acid), 2-hydroxyoctanoic acid or 4-oxopentanoic acid. The composition according to claim 1, wherein Z of the compound of the formula (IV) is S. The composition according to claim 20, wherein R ⁴ of the compound of formula (IV) is C _1-6 alkyl. Compounds of formula (IV) include methyl isothiocyanate, substituted methyl isothiocyanate, ethyl isothiocyanate, substituted ethyl isothiocyanate, propyl isothiocyanate, substituted propyl isothiocyanate, butyl isothiocyanate, t-butyl isothiocyanate, substituted butyl isothiocyanate, The composition according to claim 21, which is a pentyl isothiocyanate, a substituted pentyl isothiocyanate, a hexyl isothiocyanate or a substituted hexyl isothiocyanate. 22. The composition of claim 22, wherein the propyl isothiocyanate is an isopropyl isothiocyanate. The composition according to claim 22, wherein the butyl isothiocyanate is t-butyl isothiocyanate. 22. The composition of claim 22, wherein the substituted butyl isothiocyanate is 1-isothiocyanate-4-methylsulfinylbutane. The composition according to claim 20, wherein R ⁴ of the compound of formula (IV) is C _2-6 alkenyl. The compounds of formula (IV) are ethenylisothiocyanate, substituted ethenylisothiocyanate, propenylisothiocyanate, substituted propenylisothiocyanate, butenylisothiocyanate, substituted butenylisothiocyanate, pentenylisothiocyanate, substituted pentenylisothiocyanate, hexenyliso The composition according to claim 26, which is a thiocyanate or a substituted hexenyl isothiocyanate. The composition according to claim 27, wherein the propenyl isothiocyanate is allyl isothiocyanate. The composition according to claim 20, wherein R ⁴ of the compound of formula (IV) is C _1-6 arc-aryl. 29. The composition of claim 29, wherein the compound of formula (IV) is benzyl isothiocyanate, substituted benzyl isothiocyanate, phenethyl isothiocyanate, substituted phenethyl isothiocyanate, 3-phenylpropyl isothiocyanate or substituted 3-phenylpropyl isothiocyanate. Stuff. ^{R 4} of the compound of formula (IV), is aryl A composition according to claim 20. The composition according to claim 31, wherein the compound of formula (IV) is phenyl isothiocyanate or substituted phenyl isothiocyanate. The composition of claim 32, wherein the substituted phenyl isothiocyanate is substituted with halogen, C _1-6 alkoxy or C _1-6 alkyl. The composition according to claim 1, wherein Z of the compound of formula (IV) is O. ^{R 4} of the compound of formula (IV) _is a _{C 1 to 6} alkyl, A composition according to claim 34. The compound of formula (IV) is methyl isocyanate, substituted methyl isocyanate, ethyl isocyanate, substituted ethyl isocyanate, propyl isocyanate, substituted propyl isocyanate, butyl isocyanate, substituted butyl isocyanate, pentyl isocyanate, substituted pentyl isocyanate, hexyl isocyanate or substituted hexyl isocyanate. The composition according to claim 35. The composition according to claim 36, wherein the propyl isocyanate is an isopropyl isocyanate. The composition according to claim 36, wherein the butyl isocyanate is t-butyl isocyanate. ^{R 4} of the compound of formula (IV) _is a _{C 2 to 6} alkenyl, composition according to claim 34. Claimed that the compound of formula (IV) is ethenyl isocyanate, substituted ethenyl isocyanate, propenyl isocyanate, substituted propenyl isocyanate, butenyl isocyanate, substituted butenyl isocyanate, pentenyl isocyanate, substituted pentenyl isocyanate, hexenyl isocyanate or substituted hexenyl isocyanate. Item 39. The composition according to claim 40, wherein the propenyl isocyanate is an allyl isocyanate. ^{R 4} of the compound of formula _{(IV), C 1 to 6} alk - aryl A composition according to claim 34. The composition according to claim 42, wherein the compound of formula (IV) is a benzyl isocyanate, a substituted benzyl isocyanate, a phenethyl isocyanate, a substituted phenethyl isocyanate, a 3-phenylpropyl isocyanate or a substituted 3-phenylpropyl isocyanate. ^{R 4} of the compound of formula (IV), is aryl A composition according to claim 34. The composition according to claim 44, wherein the compound of formula (IV) is phenylisocyanate or substituted phenylisocyanate. The composition according to claim 45, wherein the substituted phenylisocyanate is substituted with a halogen, C _1-6 alkoxy or C _1-6 alkyl. The composition according to claim 1, which is anhydrous. The composition according to claim 1, further comprising water. The composition according to claim 1, further comprising a second therapeutic agent which is an anticancer drug. The composition according to claim 49, wherein the anticancer drug is SM88. The composition of claim 1, further comprising one or more components of SM88. The composition according to claim 1, wherein the ratio of the compound of formula (I) to the amide of formula (III) is about 10: 1. A method comprising applying the composition of claim 1 to mammalian skin or mucosa for a time sufficient to achieve penetration of the therapeutic agent of formula (IV) through at least a portion of the skin or mucous membrane. .. Nona Ethylene Glycol Monododecyl Ether,
1-Methyl-2-pyrrolidone,
ethanol,
With linoleic acid, and allyl isothiocyanate, 1-isothiocyanato-4-methylsulfinyl butane, benzyl isothiocyanate, substituted benzyl isothiocyanate, phenethyl isothiocyanate, substituted phenethyl isothiocyanate, benzyl isocyanate, substituted benzyl isocyanate, phenethyl isocyanate or substituted phenethyl isocyanate. A therapeutic agent,
It is a composition containing
The composition which allows percutaneous delivery of the therapeutic agent. The composition according to claim 54, which is anhydrous. The composition of claim 54, further comprising water. The composition according to claim 54, wherein the ratio (v / v) of nonaethylene glycol monododecyl ether to 1-methyl-2-pyrrolidone is 9: 1 to 11: 1. 54. The composition of claim 54, wherein the ratio (v / v) of nonaethylene glycol monododecyl ether to 1-methyl-2-pyrrolidone is about 10: 1. The composition of claim 54, further comprising a second therapeutic agent that is an anti-cancer agent. The composition according to claim 59, wherein the anticancer drug is SM88. 54. The composition of claim 54, further comprising one or more components of SM88. A method of treating a mammalian cancer in need of treatment for the cancer, sufficient time for the mammal to achieve permeation through the skin or mucous membrane of an effective amount of the therapeutic agent of formula (IV). The method comprising applying the composition according to any one of claims 1 to 61 to the skin or mucous membrane of the above. A method of preventing cancer in mammals that requires cancer prevention and feeding for a time sufficient to achieve penetration through the skin or mucous membranes of at least some of the therapeutic agents of formula (IV). The method comprising applying the composition according to any one of claims 1 to 61 to the skin or mucous membrane of an animal.